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<p>Mismatches in HLA haplotypes between donors and recipients significantly increase the risk of graft failure due to immune rejection. Knockout (KO) of beta-2 microglobulin (B2M) is the current standard for eliminating HLA class I (HLA-I) surface expression and protecting allogeneic products from T-cell–mediated rejection; however, complete HLA-I ablation can trigger natural killer (NK) cell “missing-self” responses and disrupt critical immune-regulatory interactions. To address these limitations, we introduced a cytomegalovirus-derived US2 encoding sequence into the <i>AAVS1</i> safe-harbor locus of a human induced pluripotent stem cell (hiPSC) line. Flow cytometry showed that US2 selectively abrogates HLA-A2 surface expression while retaining low levels of total HLA-I. In coculture assays, US2 expression abolished HLA-A2 alloreactive T-cell activation without increasing NK cell degranulation, indicating preserved inhibitory signaling. Together, these findings establish US2-mediated immune evasion as a refined single-edit alternative to B2M KO, enabling selective HLA-I modulation while preserving critical immune-regulatory interactions.</p>

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CRISPR-Cas9-mediated knock-in of cytomegalovirus US2 provides an alternative strategy for generating hypoimmunogenic hiPSC lines

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Juan J. Novoa,
  • Lonneke H. Gaykema,
  • Juliette A. de Klerk,
  • Janneke H. D. Peerlings,
  • Rianne Y. van Nieuwland,
  • Arno van der Slik,
  • Francijna E. van den Hil,
  • Valeria V. Orlova,
  • Manuel A. F. V. Gonçalves,
  • Cathelijne W. van den Berg,
  • Ton J. Rabelink,
  • Arnaud Zaldumbide

摘要

Mismatches in HLA haplotypes between donors and recipients significantly increase the risk of graft failure due to immune rejection. Knockout (KO) of beta-2 microglobulin (B2M) is the current standard for eliminating HLA class I (HLA-I) surface expression and protecting allogeneic products from T-cell–mediated rejection; however, complete HLA-I ablation can trigger natural killer (NK) cell “missing-self” responses and disrupt critical immune-regulatory interactions. To address these limitations, we introduced a cytomegalovirus-derived US2 encoding sequence into the AAVS1 safe-harbor locus of a human induced pluripotent stem cell (hiPSC) line. Flow cytometry showed that US2 selectively abrogates HLA-A2 surface expression while retaining low levels of total HLA-I. In coculture assays, US2 expression abolished HLA-A2 alloreactive T-cell activation without increasing NK cell degranulation, indicating preserved inhibitory signaling. Together, these findings establish US2-mediated immune evasion as a refined single-edit alternative to B2M KO, enabling selective HLA-I modulation while preserving critical immune-regulatory interactions.